Biology subjects

Labadie, B.

Publications and source records attributed to Labadie, B..

3 recordsLinked to original sources

bioRxiv2023

Androgen blockade primes NLRP3 in macrophages to induce tumor phagocytosis

Immune-based therapies induce durable remissions in subsets of patients across multiple malignancies. However, there is limited efficacy of immunotherapy in metastatic castrate-resistant prostate cancer (mCRPC), manifested by an enrichment of immunosuppressive (M2) tumor- associated macrophages (TAM) in the tumor immune microenvironment (TME). Therefore, therapeutic strategies to overcome TAM-mediated immunosuppression are critically needed in mCRPC. Here we discovered that NLR family pyrin domain containing 3 (NLRP3), an innate immune sensing protein, is highly expressed in TAM from metastatic PC patients treated with standard-of-care androgen deprivation therapy (ADT). Importantly, ex vivo studies revealed that androgen receptor (AR) blockade in TAM upregulates NLRP3 expression, but not inflammasome activity, and concurrent AR blockade/NLRP3 agonist (NLRP3a) treatment promotes cancer cell phagocytosis by immunosuppressive M2 TAM. In contrast, NLRP3a monotherapy was sufficient to enhance phagocytosis of cancer cells in anti-tumor (M1) TAM, which exhibit high de novo NLRP3 expression. Critically, combinatorial treatment with ADT/NLRP3a in a murine model of advanced PC resulted in significant tumor control, with tumor clearance in 55% of mice via TAM phagocytosis. Collectively, our results demonstrate NLRP3 as an AR-regulated "macrophage phagocytic checkpoint", inducibly expressed in TAM by ADT and activated by NLRP3a treatment, the combination resulting in TAM-mediated phagocytosis and tumor control.

cancer biology↗

bioRxiv2023

Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis

PurposePTEN loss-of-function/PI3K pathway hyperactivation occurs in [~]50% of metastatic, castrate-resistant prostate cancer patients, resulting in poor therapeutic outcomes and resistance to immune checkpoint inhibitors across multiple malignancies. Our prior studies in prostate-specific PTEN/p53-deleted genetically engineered mice (Pb-Cre;PTENfl/flTrp53fl/fl GEM) with aggressive-variant prostate cancer (AVPC) demonstrated feedback Wnt/{beta}-catenin signaling activation in 40% mice resistant to androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki)/PD-1 antibody (aPD-1) combination, resulting in restoration of lactate cross-talk between tumor-cells and tumor-associated macrophages (TAM), histone lactylation (H3K18lac) and phagocytic suppression within TAM. Here, we targeted immunometabolic mechanism(s) of resistance to ADT/PI3Ki/aPD-1 combination, with the goal of durable tumor control in PTEN/p53-deficient PC. Experimental designPb-Cre;PTENfl/flTrp53fl/fl GEM were treated with either ADT (degarelix), PI3Ki (copanlisib), aPD-1, MEK inhibitor (trametinib) or Porcupine inhibitor (LGK 974) as single agents or their combinations. MRI was used to monitor tumor kinetics and immune/proteomic profiling/ex vivo co-culture mechanistic studies were performed on prostate tumors or established GEM-derived cell lines. ResultsWe tested whether Wnt/{beta}-catenin pathway inhibition with LGK 974 addition to degarelix/copanlisib/aPD-1 therapy enhances tumor control in GEM, and observed de novo resistance due to feedback activation of MEK signaling. Based on our observation that degarelix/aPD-1 treatment resulted in partial inhibition of MEK signaling, we substituted trametinib for degarelix/aPD-1 treatment, and observed a durable tumor growth control of PI3Ki/MEKi/PORCNi in 100% mice via H3K18lac suppression and complete TAM activation within TME. ConclusionsAbrogation of lactate-mediated cross-talk between cancer cells and TAM results in durable ADT-independent tumor control in PTEN/p53-deficient AVPC, and warrants further investigation in clinical trials. STATEMENT OF TRANSLATIONAL RELEVANCEPTEN loss-of-function occurs in [~]50% of mCRPC patients, and associated with poor prognosis, and immune checkpoint inhibitor resistance across multiple malignancies. Our prior studies have demonstrated that ADT/PI3Ki/PD-1 triplet combination therapy controls PTEN/p53-deficient PC in 60% of mice via enhancement of TAM phagocytosis. Here, we discovered that resistance to ADT/PI3K/PD-1 therapy occurred via restoration of lactate production via feedback Wnt/MEK signaling following treatment with PI3Ki, resulting in inhibition of TAM phagocytosis. Critically, co-targeting of PI3K/MEK/Wnt signaling pathways using an intermittent dosing schedule of corresponding targeted agents resulted in complete tumor control and significantly prolonged survival without significant long-term toxicity. Collectively, our findings provide "proof-of-concept" that targeting lactate as a macrophage phagocytic checkpoint controls growth of murine PTEN/p53-deficient PC and warrant further investigation in AVPC clinical trials.

cancer biology↗

bioRxiv2022

Reversal of lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer

PTEN loss-of-function occurs in approximately 50% of mCRPC patients, and is associated with a poor prognosis, therapeutic outcomes and resistance to immune-checkpoint inhibitors. Recent clinical studies demonstrated that dual PI3K/AKT pathway inhibition and androgen axis blockade led to a modest improvement in progression-free survival of PTEN-deficient mCRPC patients, but the mechanistic basis for this limited efficacy is unknown. To elucidate potential resistance mechanism(s), we performed co-clinical trials in a prostate-specific PTEN/p53-deficient genetically-engineered mouse model, and discovered that the recruitment of PD-1-expressing tumor-associated macrophages (TAM) thwarts the phagocytosis-mediated anti-tumor efficacy of androgen deprivation therapy (ADT)/PI3K inhibitor (PI3Ki) combination. Strikingly, we observed a TAM-dependent [~]3-fold enhancement in the overall response rate with the addition of PD-1 antibody (aPD-1) to ADT/PI3Ki combination therapy. Mechanistically, decreased lactate production from PI3Ki-treated tumor cells suppressed histone lactylation (H3K18lac) within TAM, resulting in their phagocytic activation, which was augmented by concurrent ADT/aPD-1 treatment. Consistent with our murine observations, single cell RNA-sequencing analysis of human metastatic PC samples revealed a direct correlation between high glycolytic activity and phagocytosis suppression. Critically, feedback activation of Wnt/{beta}-catenin signaling observed in non-responder mice following ADT/PI3Ki/aPD-1 combination treatment, restored lactate-mediated H3K18lac and suppressed phagocytosis within macrophages. Altogether, these data suggest that reversal of lactate and PD-1-mediated TAM immunosuppression by PI3Ki and aPD-1, respectively, controls tumor growth in combination with ADT, and warrants further clinical investigation in PTEN/p53-deficient mCRPC patients. One Sentence SummaryInhibition of tumor-cell intrinsic lactate production suppresses PTEN/p53-deficient prostate cancer growth via macrophage activation/phagocytosis

cancer biology↗